生物活性

• 靶点

  CFTR (F508del) EC50:25nM

  CFTR (G551D) EC50:100nM

• 描述Cystic fibrosis transmembrane conductance regulator (CFTR) is a protein kinase A-activated epithelial anion channel that is responsible for salt and fluid transport in multiple organs. Ivacaftor is a potent potentiator of CFTR. It increases forskolin-stimulated CFTR-mediated transepithelial current (I_T) with an EC₅₀ of 100 ± 47 nM in G551D-FRT cells. Also in F508del-FRT cells, ivacaftor increased forskolin-stimulated I_T with an EC₅₀ of 25 ± 5 nM. In recombinant cells expressing G551D-, F508del-, or wild-type (WT)-CFTR, 10 μM ivacaftor increased their CFTR channel open probability by ~6-fold, ~5-fold and ~2-fold, respectively. Treatment of ivacaftor significantly increased the forskolin-stimulated I_T in F508del human bronchial epithelia (HBE) cells with an EC₅₀ of 22 ± 10 nM. G551D/F508del HBE cells treated with 10μM ivacaftor for 5 days showed significant increased cilia beat frequency compared with vehicle-treated controls^[1]. In the analysis of ATP-independent activity for WT-CFTR, 200 nM ivacaftor increased the activity by 2-fold, as determined by the ratio of post washout ATP-independent current to the robust ATP-induced current^[2]. The bilayer studies of WT-CFTR showed that the open probability of CFTR channel treated with both 1 mM Mg-ATP and 2 μM ivacaftor was approximately twice that measured in the presence of Mg-ATP alone. The treatment of 10 μM ivacaftor on liposomes containing phosphorylated F508del-CFTR or phosphorylated G551D-CFTR increased iodide-mediated flux in the presence of 1 mM Mg-ATP^[3].
• 作用机制Ivacaftor potentiates CFTR function by increasing the open time of WT-CFTR, stabilizing a post-hydrolytic open state, thereby promoting decoupling between the gating cycle and ATP hydrolysis cycle^[2].

• 动物研究
  剂量	Rat: 10 mg/kg - 50 mg/kg[4] (p.o.) Dog: 60 mg/kg[4] (p.o.)
  给药途径	p.o.